Research Program

Figure 1 The structure of PAH. (a) The annotated domain structure of mammalian PAH. (b) The 2.9 Å PAH crystal structure in orthogonal views, colored as in part a, subunit A is shown in ribbons; subunit B is as a C-alpha trace; subunit C is in sticks; and subunit D is in transparent spheres. In cyan the subunits are labeled near the catalytic domain (top); in red they are labeled near the regulatory domain (bottom). The dotted black circle illustrates the autoregulatory domain partially occluding the enzyme active site (iron, in orange sphere). (c) Comparison of the subunit structures of full length PAH and those of the composite homology model; the subunit overlay aligns residues 144-410. The four subunits of the full length PAH structure (the diagonal pairs of subunits are illustrated using either black or white) are aligned with the two subunits of 2PAH (cyan) and the one subunit of 1PHZ (orange). The catalytic domain is in spheres, the regulatory domain is in ribbons, and the multimerization domain is as a C-alpha trace. The arrow denotes where the ACT domain and one helix of 2PAH conflict.

A structural roll of the dice

Morpheeins challenge a protein-folding paradigm

An unusual phylogenetic variation in the active site and allosteric metal ions of PBGS

The equilibrium of morpheein forms observed for human PBGS

Three models for allosteric regulation

Targeting morpheeins for drug design or discovery

Education and Training

Educational Background

Postdoctoral, Chemistry/Enzymology, Harvard University, 1979-1981

PhD, Biochemistry, University of Pennsylvania, 1979

BS, Chemistry, State University New York, Cortland, 1975

Memberships

American Chemical Society 1975 - present

American Society for Biochemistry and Molecular Biology, 1986 - present

Multimer-specific surface cavities as targets for the discovery of allosteric modulators (e.g. drugs)

Lab Overview

The Jaffe Laboratory studies protein structure-function relationships using both biochemical and biophysical approaches. We are focused on the roles of protein quaternary structure dynamics in the control of protein function. This follows our discovery that multimeric proteins can come apart, the dissociated units can change conformation, and these altered conformations can come back together differently to form a structurally and functionally distinct assembly.

Unlike amyloid, the changes in subunit structure are subtle, such as a hinge movement between folded domains, the oligomeric stoichiometry is finite, and the process is freely reversible. This structural dynamic can be the basis for allosteric regulation of protein function (the morpheein model of protein allostery). Disregulation of the equilibrium of assemblies is responsible for some human disease. Designed regulation of the equilibrium of assemblies provides a basis for allosteric drug discovery. The now well-established structural dynamic was originally unexpected, but new examples are being discovered regularly, as in the Ebola virus VP40 protein (E. Ollmann-Saphire, Scripps Institute). Although we coined the term morpheein to describe proteins that could reversibly dissociate, change conformation and assemble differently with finite stoichiometry, the term "transformers" has also been used. What we have learned from the prototype morpheein, porphobilinogen synthase, allows us to mine the literature and protein structure databases in search of other proteins that function as morpheeins. A family of putative morpheeins includes many drug targets, including cancer chemotherapeutic targets. The putative morpheein currently under most active investigation in the laboratory is phenylalanine hydroxylase, where the dysregulation of the interchange between various multimers is proposed to account for phenylketonuria in some patients.

Related News

PHILADELPHIA (February 16, 2016) – Phenylketonuria, also known as PKU, is the most common inherited disease affecting amino acid metabolism. In a study published February 15th in Proceedings of the National Academy of Sciences, Fox Chase Cancer Center – Temple Health researchers made tremendous strides toward that goal by shedding new light on the structure of phenylalanine hydroxylase (PAH)—the enzyme that is defective in PKU patients.

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